Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. B), 91-104
Clinical safety and tolerance of cefoxitin sodium: an overview
C. van Winzum
Based on data from 108 studies conducted throughout the world in 2277 patients, 1924 of whom received cefoxitin (i.v. in 1749 patients and i.m. in 175), it is concluded that parenterally administered cefoxitin sodium is well tolerated by the majority of patients (more than 90%). Drug-related adverse clinical reactions occurred in about 8 % of the patients. The adverse clinical experiences most frequently observed were rash (2-2% incidence) and local intolerance, including thrombophlebitis, at the site of administration (5-3% incidence). From laboratory data related to haematopoietic, renal, and hepatic functions, it appears that cefoxitin has neither unusual nor significant toxic effects on the major body systems. During therapy with cefoxitin, some patients developed a positive direct Coombs test (2-4%), eosinophilia (2-9%), or an increase in liver enzymes (ca. 3%).
Introduction Cefoxitin sodium is the first of the cephamycins, a new group of /f-lactam antibiotics. A unique feature of cefoxitin is its remarkable resistance to inactivation by yS-lactamases (Onishi, Daoust, Zimmerman, Hendlin & Stapley, 1974; Wallick & Hendlin, 1974; Darland & Birnbaum, 1977). In the animal species studied, large doses of parenterally administered cefoxitin were well tolerated; the antibiotic had the degree of safety characteristic of the presently available /Mactam antibiotics (preclinical and toxicologic data on file at Merck Sharp & Dohme Research Laboratories). Cefoxitin was well tolerated by the 58 healthy volunteers who received it in six Phase I clinical pharmacology studies. After single intravenous doses of 0-5, 1 0 and 2 0 g of cefoxitin, adverse clinical reactions were reported for 4 subjects. None of these was serious. It was observed in these Phase I studies that cefoxitin reconstituted in water was not well tolerated at the injection site after single intramuscular doses of 0-5 or 10 g. Reconstitution of cefoxitin in 0-5% lidocaine HC1 improved tolerance to cefoxitin at the site of i.m. injection significantly; use of 1 0 % lidocaine HC1 did not further improve local tolerance. The majority of subjects studied had no pain or only mild pain at the injection site after i.m. doses of 0-5,1 0 or 2 0 g of cefoxitin reconstituted in 0-5 or 1 -0 % lidocaine HC1 (Schrogie et al., 1978). The safety and tolerance of cefoxitin were evaluated on the basis of data from 108 clinical studies conducted throughout the world, involving a total of 2277 patients. All 1924 patients who received cefoxitin parenterally (Table I) have been included in the analyses of safety and tolerance. 91
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Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey, U.S.A.
92
C. van Winzum Table I. Total patient population Nu m
, Jer of studies
Nature of study Comparative i.v. studies Outside U.S.A.
21 6 6 6
Number of patients Cefoxitin Cephalothin Cefazolin
3,3
Noncomparative i.v. studies Outside U.S.A. Within U.S.A. Subtotal noncomparative studies
27 37 27 37 64 64
430 931 430 931 1361 1361
— — — —
— — —
430 931 1361
Subtotal i.v. studies
97 97
1749
290 290
63
2102
9 9 22
147 147 28 28 1924
— — — 290
— — 63
147 28 2277
Noncomparative studies Outside U.S.A. i.m. Outside U.S.A. i.v.—i.m. Total
108
107 107 290 290
— 63
371 123
—
247
63
741
The results presented in the report relate only to clinical experience with dry, microcrystalline sodium cefoxitin, the pharmaceutical formulation that will be marketed. This formulation is stable for at least 2 years when stored below 30° in the dry state. The data analyzed for this report exclude patients whose case records had not been received in the head office of Merck Sharp & Dohme Research Laboratories by 15 July 1977, for studies performed overseas, and by 15 November 1977, for studies performed within the United States. Patient population and methods
The total number of studies conducted throughout the world and the numbers of patients in the various treatment groups are shown in Table I. The total of 1749 patients who received cefoxitin i.v. included 1361 who participated in the 64 noncomparative studies and 388 who were in cefoxitin-treated groups of the 33 comparative studies (versus cephalothin or cefazolin). In 5 of the 6 studies performed within the U.S.A., the randomization procedure specified in the study protocol was not followed. Consequently, the two treatment groups in the U.S.A. studies differed in some important aspects in a statistically significant way: the incidence of background diseases, physiologic impairments, or both, was higher in the cefoxitin-treated group than in the cephalothin-treated gTOup. Alcoholism, neoplastic disease, negative nitrogen balance, and renal insufficiency were present in a significantly higher proportion of cefoxitin-treated patients. These differences are explained by the fact that an excess of approximately 30 seriously ill patients was enrolled in the cefoxitin-treated group. Of these 30 patients, 22 were suffering from infection by cephalothin-resistant, often multiresistant, cefoxitin-sensitive
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Subtotal comparative studies
188 60 140 140 388 388
Within U.S.A.
183 183
Total
Safety and tolerance of cefoxitin
93
Results Intravenous studies a. Incidence of adverse clinical experiences. The overall incidence of adverse clinical experiences in the i.v. comparative and noncomparative studies is summarized in Table II. Adverse clinical experiences that the investigators considered to be drug related (possible, probable, or definite relationship) were reported for 138 (7-9%) of the 1749 cefoxitin-treated patients, compared with 29 (10 %) of the 290 cephalothin-treated patients and 10 (15-9%) of the 63 cefazolin-tTeated patients.
Table II. Overall incidence of adverse clinical experiences in i.v. comparative and noncomparative studies with cefoxitin, cephalothin and cefazolin Total number of patients
Cefoxitin 1749
Cephalothin
Cefazolin
290
63
Number of patients with non-drug-related adverse experiences Number of patients with drug-related* adverse experiences
166(9-5%)
17(5-9%)
2(3-2%)
138(7-9%)
29(10-0%)
10(15-9%)
Total number of patients with adverse experiences
304(17-4%)
46(15-9%)
12(19-1%)
•Drug related: possibly, probably, or definitely related to study drug, in the opinion of the investigator.
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pathogens. In the context of these comparative studies, these patients could only be treated with cefoxitin. In the comparative studies, patients were to be selected in such a way that they could receive either cefoxitin or the control agents, since allocation of patients to treatment groups was randomized. This meant that the causal pathogens had to be sensitive to both cefoxitin and the control agent, cephalothin or cefazolin. As a consequence, the 741 patients of the comparative studies were, in general, less severely ill—in terms of infections disease and of complicating background conditions—than the 1361 patients of the noncomparative studies. The safety and tolerance of i.m. cefoxitin were evaluated on the basis of data from 11 clinical studies conducted overseas, involving a total of 175 patients. In 9 of these studies, a total of 147 patients was treated with i.m. cefoxitin. In the remaining 2 studies, a total of 28 patients was treated first with i.v. cefoxitin (5 to 7 days) and then with i.m. cefoxitin. The severity of illness in the 175 patients who received i.m. cefoxitin was, in general, mild to moderate. The dosage of i.v. cefoxitin was, in the majority of patients, 2 g (range 1 to 4 g) every 8 h. In the comparative studies, i.v. cephalothin was also given at that dosage and on the same schedule, but the dosage of i.v. cefazolin was 1 g every 8 h in almost all patients. The infusion time for these antibiotics was 30 min (range 5 to 120 min) in the majority of patients. The mean duration of i.v. treatment was about 8 days (range 5 to 14 days) in most patients. Cefoxitin was reconstituted in 0-5 or 1 0 % lidocaine HC1 solution for i.m. administration at a dosage of 1 g every 8 h. The mean duration of i.m. treatment was about 7 days (range 3 to 14 days).
Table III. Studies with intravenous cefoxitin. Drug-related adverse experiences, by body system and intensity Total at Patients Patients Patients
Treatment group—cefoxitin 1749 1749 1611 (921%) 138 (7-9%)
study start in time range without adverse experience with any adverse experience
Adverse experiences by body system
Moderate
Severe
— 1 2 7
2 19
1 2 3 1 1 1 1 5 16
2 1
4 1
—
— 1 1
—
—
Total
Per cent
22 1 3 6 1
46 7 39 1
1-3 01 01 0-3 0-6 01 01 01 01 2-6 0-4 2-2 01
3 2 1
0-2 01 01
57
3-3 01 01 01 01 0-2 01 01 2-2 01 01 0-5 0-2 01 01 01 01
1 1 3 1
\
13
3 1
3 2 1
3 1 1 1
38 1 2 8 3 2 1 1 2
1 1 22 2 2
1 — 1 6
1 1 —
—
7 3 5
1 — — 1
— 1 — 1
20 1 13 3 5 1 1 1
11 01 0-7 0-2 0-3 01
2 1 1
01 01
01 01
01
Note: This table contains counts of patients; although a patient might have had two or more adverse experiences for one body system, he was counted only once in that body system total. Therefore, the sum of individual adverse experiences may not equal the total for the body system. A similar distinction exists between the body system totals and the number of patients with adverse experiences.
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Body as a whole Chest pain Oedema Fever Headache Pain—back Drug fever Hypersensitivity Infection, fungal Integumentary system Pruritus Rash Stomatitis Respiratory system Dyspnoea Hyperventilation Cardiovascular system Arrhythmia Bradycardia Cyanosis Hypertension Hypotension Palpitations Tachycardia Thrombophlebitis Angina pectoris Vasodilation Infused vein—pain Infused vein—induration Infused vein—erythema Infused vein—exudation Infused vein—inflammation Infused vein—infection Digestive system Constipation Diarrheoa Nausea Vomiting Tongue discoloration Urogenital system Renal failure Nervous system Dizziness Vertigo
No. of points with recorded maximum intensity
Mild
95
Safety and tolerance of cefoxitin
All drug-related adverse clinical experiences reported for the 1749 patients treated with i.v. cefoxitin are further specified by body system and by severity (maximum recorded intensity) in Table III. All drug-related adverse clinical experiences reported in the comparative studies are similarly specified in Table IV for the cephalothin-controlled studies and in Table V for the cefazolin-controlled studies. Table IV. Cefoxitin and cephalothin. Drug-related adverse clinical experiences in 27 Phase II and Phase III comparative i.v. studies in the U.S.A. and overseas Cefoxitin
290
328
Total patients Patients with any adverse experience
29(10%)
Adverse experiences by body system
Pts. c max. intensity Mi Mod Sev Tot %
21 (6-4%)
Body as a whole Chills Oedema Fever Pain in back
3 1
10 0-3
3
10
1 3 1
0-3 0-9 0-3
Integumentary system Rash Erythema multiforme Glossitis/black tongue
6 4 1 1
20
3 3
0-9 0-9
Musculoskeletal system Myalgia "
1 1
0-3 0-3
1 1
0-3 0-3
00
Pts. c max. intensity Mi Mod Sev Tot % 1-2
1-4 0-3 0-3
Respiratory system Dyspneoa 12 1
Blood/lymph system Phlebitis
2-4 2-4
Digestive system Diarrheoa Vomiting Urogenital system Renal failure Nephritis
3 2 1
2-4 0-3 0-3 0-9
2
2 1 1
4 1 1
1-2 0-3 0-3
2
1
7 7
21 21
1 1
0-3 0-3
1 1
0-3 0-3
41 10 0-3 20 1-4 10 0-3
1 1 2
1 1
Ul — —
Cardiovascular system Cyanosis Hypotension Thrombophlebitis Thrombosis Infused vein—pain Infused vein—induration Infused vein—erythema Infused vein—irritation
1
10 0-7 0-3
2
1
0-3
1 1
0-3
See note on Table III. Mi, mild; Mod, moderate; Sev, severe; Tot, total.
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Cephalothin
96
C. van Winzum
Because one patient can have more than one adverse experience, the total number of incidents can exceed the number of patients. Table III shows that 167 incidents of adverse experience were reported for 138 of the 1749 patients given i.v. cefoxitin. Of the 167 incidents, 71 (43%) were clinically mild, 69 (41 %) were moderate, and 27 (16%) were severe. Table IV shows that in the comparative studies with cephalothin, 21 (6-4%) of the 328 cefoxitin-treated patients had 29 drug-related adverse clinical experiences, compared with 29 (10%) of the 290 cephalothin-treated patients, who had 40 drug-related adverse clinical experiences. The intensities of these experiences were: Mild
Moderate
Severe
Total
7 6
13 20
9 14
29 40
Table V shows that in the comparative studies with cefazolin, 6 (10%) of the 60 cefoxitintreated patients had 6 drug-related adverse clinical experiences, compared with 10 (15-8%) of the 63 cefazolin-treated patients, who had 12 drug-related adverse clinical experiences. The intensities of these experiences were: Mild 4 6
Cefoxitin Cefazolin
Moderate 1 5
Severe 1 1
Total 6 12
Table V. Cefoxitin and cefazolin. Drug-related adverse clinical experiences in 6 Phase II comparative i.v. studies overseas
Total patients Patients with any adverse experience Adverse experiences by body system
Cefoxitin
63
60
10(15-8%)
6(10%)
Pts. c max. intensity Mi Mod Sev Tot % — 1
Body as a whole Fever Hypersensitivity Integumentary system Rash Stomatitis
Cefazolin
1 1
— 3
1
4 4
1-6 1-6 6-3 6-3
Pts. c max. intensity Mod Sev Tot % —
1
1-7
1
1
1-7
—
2 1 1
3-3 1-7 1-7
1
1 — 1
1 1
1-6 1-6
— 2
5 5
7-9 7-9
Digestive system Diarrheoa
—
0
Psychiatric Depression
— 1
Respiratory system Dyspneoa Cardiovascular system Thrombophlebitis Vasodilation
Mi
3
0
—
2 1 1
3-3
1 1
1-7 1-7
1 1 — 1
1 1
—
1-6 16
Sec note on Table 111. Mi, mild; Mod, moderate; Sev, severe; Tot, total.
1-7 1-7
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Cefoxitin Cephalothin
Safety and tolerance of cefoxitin
97
Table VI. Mortality in all studies Cefoxitin Type of study Comparative i.v. Noncomparative i.v. Subtotal i.v. l.m.
Total
Cephalothin
Cefazolin
No. of patients
Deaths
No. of patients
Deaths
18(4-6%) 88(6-5%) 106(61%) 2(11%)
290
10(3-4%)
63
1(1-6%)
290
10(3-4%)
63
1(16%)
108(5-6%)
290
10(3-4%)
63
1(16%)
No. of patients
Deaths
388 1361 1749 175 1924
Relationship of cefoxitin treatment to death could not be excluded in 1 case, a 37-yearold man with metastatic choriocarcinoma and renal thrombosis who developed signs of renal insufficiency post-operatively. He also received canceT chemotherapy. The patient died of renal failure several days after cefoxitin treatment had been discontinued. No autopsy was performed. Mortality in the comparative studies was 4-6% in the cefoxitin group, 3-4% in the cephalothin group, and 1 -6% in the much smaller cefazolin group. Mortality in the noncomparative studies, which involved more severely ill patients, was, as expected, slightly higher (6-5%) than, in the comparative studies. Because evaluation of the therapeutic utility of cefoxitin in 'problem' patients was emphasized in studies in specialized centers in the U.S.A., the mortality rate was higher in i.v. studies in the U.S.A. than in i.v. studies overseas: Number of patients Number of deaths
U.S.A. 1071 89(8-3%)
Overseas 678 17(2-5%)
Total 1749 106(61%)
c. Discontinuation of treatment because of adverse clinical experiences. Treatment was discontinued because of adverse clinical experiences in 69 (3-9%) of the 1749 patients
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These data show that cefoxitin was, in general, at least as well tolerated as were cephalothin and cefazolin at equipotent i.v. daily dosages. b. Mortality. An i.v. antibiotic, such as cefoxitin, will frequently have to be administered to severely ill, often terminally ill, patients, or to patients with impaired immune response caused by metastatic malignancies, severe diabetes mellitus, renal insufficiency, or the use of immunosuppressive drugs. In order to gain broader experience with the potential utility of cefoxitin in the treatment of such conditions, studies were conducted in specially selected institutions having infectious-disease units, particularly in the United States. These studies included patients with infections caused by Bacteroides fragilis and cephalothin-resistant, cefoxitin-sensitive aerobic pathogens. Inevitably, a number of patients did not survive, despite appropriate antibiotic treatment (Table VI). As Table VI shows, 106 (61 %) of the 1749 patients who received i.v. cefoxitin died, either during treatment or within 14 days after discontinuation of cefoxitin treatment. In 86 of these patients, death was due primarily to the severe background disease; in 19 patients, death was due primarily to the infection, although serious background disease may have played a contributory role in at least 12 of these patients.
98
C van Winzum
Table VII. Intravenous cefoxitin. Discontinuation of treatment with cefoxitin because of drug-related adverse clinical experiences Adverse experience Rashes Local intolerance Pruritus Nausea-vomiting Diarrheoa Fever Other Total
Number of patients 27(1-5%) 11(0-6%) 4 3 2 5 5 57/1749(3-3%)
As may be seen in Table III, the majority of drug-related adverse clinical experiences in patients who received i.v. cefoxitin related to the body as a whole, to the integumentary system, and to the cardiovascular system. Body as a whole Special precautions were taken to avoid anaphylactoid reactions. In the course of these clinical studies, 3 patients exhibited adverse clinical effects that were initially reported as anaphylactic reactions. Each event was investigated promptly and vigorously. Follow-up studies included chest X-rays, electrocardiogram, radioisotope lung scan, and serum enzyme determinations. On the basis of these studies, it became apparent that these 3 patients had not had anaphylactic reactions, but pulmonary embolisms that gave rise to clinical signs closely resembling those of anaphylaxis. No confirmed anaphylactic reaction has yet been reported. Fever of different intensities occurred in 6 (0-3%) of the 1749 patients. Drug feveT, specifically, was reported in 1 patient (01 %), and use of cefoxitin in that patient was discontinued. Headache occurred in 11 patients (0-6%) and was mild or moderate in 10 of these. All 11 incidents of headache were reported from a single study. Integumentary system Forty-six (2-6%) of the 2749 patients had adverse experiences involving the integumentary system. Rash was the most common of these, occurring in 39 patients (2-2%). The
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who received i.v. cefoxitin. These adverse experiences were considered to be drug related (possible, probable, or definite relationship) in 57 of the 69 patients (Table VII). Rashes in 27 patients and intolerance at the infusion site in 11 patients were the most frequently cited reasons for discontinuing i.v. cefoxitin therapy. In the comparative i.v. studies with cephalothin, treatment was discontinued in 5 (1-5%) of the 328 cefoxitin-rreated patients and in 5 (1-7%) of the 290 cephalothintreated patients because of adverse clinical experiences. In the comparative i.v. studies with cefazolin, treatment was discontinued because of adverse clinical experiences in 3 (50%) of the 60 cefoxitin-treated patients and in 4 (6-3%) of the 63 cefazolin-treated patients. These results support the view that cefoxitin is not appreciably different from cephalothin and cefazolin in the frequency with which treatment had to be discontinued because of adverse clinical experiences.
Safety and tolerance of cefoxitin
99
Cardiovascular system Adverse clinical experiences affecting the cardiovascular system were reported in 57 (3-3 %) of the 1749 patients (68 separate incidents). The majority of these events (55) were local intolerance reactions that were categorized by the investigators as adverse clinical experiences. Thirty-eight patients (2-2%) developed thrombophlebitis of the infused vein. Other patients had pain, induration, erythema, exudation, inflammation, or infection at the site of infusion, sometimes with thrombophlebitis. Local tolerance of cefoxitin is discussed in more detail elsewhere in this report. Other adverse clinical experiences affecting the cardiovascular system were: angina pectoris, cyanosis, hypertension, palpitations, and bradycardia, each occurring in 1 patient (0 1%); hypotension in 4 patients (0-2%); and vasodilation in 2 patients (0-1 %). Treatment was discontinued in all the aforementioned patients except 1 with hypertension and 1 with vasodilation. Digestive system Twenty (1 -1 %) of the 1749 patients had adverse reactions involving the digestive system. Diarrheoa of mild or moderate intensity was most common, occurring in 13 patients (0-7%), and caused discontinuation of treatment in 2 patients. Nausea of moderate intensity occurred in 3 patients (0-2%), leading to discontinuation of treatment in all. Moderate vomiting occurred in 5 patients (0-3%), 2 of whom were taken off treatment. Mild 'tongue discoloration* occurred in 1 patient (01 %). Other body systems Adverse experiences affecting other body systems were uncommon. The nervous system was involved in 2 patients (01 %) and the respiratory system in 3 (0-2%). There were no reports of adverse experiences affecting the musculoskeletal, haematologic/lymphatic, or endocrine systems. No drug-related psychiatric disturbances weTe reported. The 1 patient who developed renal failure that may have been related to cefoxitin was discussed earlier in the section entitled 'Mortality'. Local tolerance of i.v. cefoxitin therapy It is well known that i.v. infusions of most ^-lactam antibiotics produce local reactions, including thrombophlebitis, in a small proportion of patients treated for several days. As part of the evaluation of cefoxitin, investigators assessed each patient's tolerance of
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typical rash exhibited by these patients was diffuse, maculopapular, and erythematous, infrequently pruritic, and transient, leaving no residual skin changes. Rashes were considered severe in 4 patients, but serious in only 1. Rashes considered related to cefoxitin led to discontinuation of therapy in 27 patients. Cefoxitin was discontinued in 4 additional patients with rashes not related to drug administration. The high proportion of patients in whom the drug was discontinued because of the development of a rash no doubt reflected the concern of investigators about hypersensitivity to (5-lactam antibiotics and, particularly, about the potentially more serious manifestations of such hypersensitivity. As mentioned earlier, anaphylaxis was not observed in the cefoxitin study population. Mild-to-moderate pruritus occurred in 7 patients (0-4%), only 1 of whom also had a rash. Cefoxitin was discontinued in 4 of these patients. Severe stomatitis developed in 1 patient (01 %).
100
C. van Winzum
Table V1D. Overall local tolerance of i.v. cefoxitin therapy Degree of tolerance
Number of patients
Phlebitis
Well tolerated Moderately well tolerated Poorly tolerated
1469(87-5%) 161(9-6%) 48(2-9%)
0 61 28
1678
89
Total
The results of the comparative studies indicated that cefoxitin was at least as well tolerated at the infusion site as cephalothin and cefazolin (Tables IV and V). Detailed analysis of the data showed that the duration of each infusion and of tetal therapy had no significant effect on the frequency or intensity of local intolerance and thrombophlebitis. Various infusion systems were used for i.v. cefoxitin therapy: indwelling polyethylene catheters; conventional i.v. systems with large-bore needles, smallbore needles, or butterfly needles; and cannulas with heparin. The data for local tolerance were, therefore, analyzed with respect to the infusion systems used. As shown in Table IX, most patients received i.v. cefoxitin either through an indwelling polyethylene catheter (514 patients) OT a butterfly needle (588 patients). Thirty-six (7 0%) of the patients given infusions through an indwelling polyethylene catheter developed thrombophlebitis, compared with 25 (4-3%) of the patients given infusions through a butterfly needle. This difference is statistically significant (P < 005). Table IX also shows that 25 (4-9%) of Table IX. Effect of infusion system on patient tolerance of i.v. cefoxitin therapy Infusion system Indwelling polyethylene catheter Large-bore needle Small-bore needle Butterfly needle Cannula with heparin Two or more systems used Totals
Well tolerated
Moderately well tolerated
Poorly tolerated
443 97 241 538 88 62
46(18)' 19(1) 32(11) 39 (20) 7(3) 18(8)
25(18) 6(2) 3(0 11 (5)
1469
161 (61)
1
2(2) 48(28)
'Numbers in parentheses indicate patients who developed thrombophlebitis.
Total 514 (36; 7%) 122 (3; 2-5%) 276 (12; 4-3%) 588 (25; 4-3%) 96(3; 31%) 82(10; 12-2%) 1678 (89; 5-3%)
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i.v. cefoxitin after therapy had been concluded. Occurrences of thrombophlebitis were also recorded. Of the 1678 patients for whom data were analyzed, i.v. infusion of cefoxitin was well tolerated by 1469 (87-5 %), moderately well tolerated by 161 (9-6%), and poorly tolerated by 48 (2-9%). Thrombophlebitis in the infused vein was reported in 89 (5-3%) of the 1678 patients: in 61 (38 %) of those patients who had tolerated cefoxitin moderately well and 28 (58 %) of those who had tolerated cefoxitin poorly (see Table Vni). Eleven patients were withdrawn from the studies because of local intolerance (Table VII). Investigators reported thrombophlebitis as an adverse clinical experience in only 38 of the 89 patients who developed signs or symptoms of thrombophlebitis, i.e., they tended to under-report this condition.
Safety and tolerance of cefoxitin
101
514 patients given infusions through an indwelling polyethylene catheter were judged by the investigators to have tolerated the infusion poorly, compared with 11 (1-8 %) of 588 patients given infusions through a butterfly needle. This difference in local tolerance is highly significant (P < 001). The incidence of thrombophlebitis in patients given infusion through an indwelling polyethylene catheter is also significantly greater (P < 001) that in all patients for whom other systems were used: 36 (7%) of 514 patients given infusions through an indwelling polyethylene catheter compared with 43 (3-9%) of 1082 patients using all other systems, as shown in Table X.
Occurrence of thrombophlebitis
Infusion system Indwelling polyethylene catheter Butterfly needle All other systems (excluding 82 patients in whom 2 or more systems were used)
Yes
No
Total
36(7-1%) 25 (4-2%)*
478(93%) 563(95-8%)
514 588
43t
1039
1082
•Indwelling catheter vs butterfly needle, P < 0 05. flndwelling catheter vs all other systems, P < 0-01.
From these data, it appears that the incidence of thrombophlebitis may be reduced and local tolerance of i.v. cefoxitin therapy can be improved if infusion through indwelling polyethylene catheters is avoided. Intramuscular studies a. Incidence and nature of adverse clinical experiences. Adverse clinical experiences were reported in 6 (3-4%) of the 175 patients admitted to these studies, and were considered drug related in 4. None of the experiences was considered serious. Therapy was discontinued in 1 patient because of adverse clinical experience considered by the investigator to be definitely related to cefoxitin therapy. A mild 'hypersensitivity reaction' was reported after 2 days of cefoxitin treatment in a 30-year-old woman with a phlegmonous infection of the right forearm. The reaction consisted of fever, intense pain in the infected arm, nausea, pruritus, maculopapular rash, and cervical lymphadenitis. After surgical drainage, the patient's clinical condition improved rapidly. Fever was reported in 2 patients, 1 of whom also had myalgia. Pruritus occurred in 1 patient. b. Mortality. Two patients died within 2 weeks after termination of cefoxitin therapy. The causes of death (myocardial infarction and stroke) were not related to cefoxitin treatment. c. Local tolerance. The investigators' oveT-all assessments of tolerance of cefoxitin at the i.m. injection site are summarized in Table XI. Intramuscular cefoxitin therapy was well tolerated by about 90% of the patients, regardless of the concentration of lidocaine diluent used to reconstitute the cefoxitin solution. No patient experienced pain on solution so severe as to require his withdrawal from the study. Investigators who initiated treatment with cefoxitin reconstituted with 0-5% lidocaine solution were permitted to change the diluent to 1 0 % lidocaine solution in ordeT to improve local tolerance. Of
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Table X. Frequency of thrombophlebitis in cefoxitln-treated patients: effect of indwelling polyethylene catheters
102
c. van Winzum Table XI. Tolerance of cefoxitin at i m. injection site Number and per cent of patients Diluent Over-all tolerance Well tolerated Moderately well tolerated Poorly tolerated Total
0-5% Lidocaine
1-0% Lidocaine
108 (92%) 8 (7%) 1 (1%)
51 (88%) 7 02%) 0
117
58
Drug-related adverse laboratory experiences (both i.v. and i.m.) Most of the changes in laboratory test values for individual patients during cefoxitin treatment were consistent with those expected during the healing of an infectious disease, such as decrease in total white blood cell count, decrease in neutrophil count, increase in lymphocyte count, and improvement in liver and kidney function test values. Because of this healing process, statistically significant within-group changes from baseline (prestudy) in the mean values of many of the laboratory tests occurred during treatment with cefoxitin, cephalothin, or cefazolin. Statistically significant between-group differences in the extent of change from baseline in the mean values of several laboratory tests occurred during treatment. In the comparative studies with cephalothin conducted outside the United States, the cefoxitintreated group showed a significantly greater decrease from baseline values in serum creatinine and a significantly greater increase in eosinophil count than did the cephalothintreated group. In the comparative studies with cephalothin conducted in the U.S.A., the cefoxitin-treated group showed a significantly greater decrease in bilirubin, a significantly greater decrease in SGOT, and a significantly greater increase in urine casts than did the cephalothin-treated group. The most frequently observed drug-related adverse laboratory experiences in the i.v. studies with cefoxitin, which are summarized in Table XII, included increased SGOT ( 3 % of the patients tested) and SGPT ( 3 1 %), eosinophilia (2-9%), and positive direct Coombs test (2-4 %). Increased haemolysis was not reported in any patient with a positive direct Coombs test. Adverse laboratory experiences led to discontinuation of i.v. cefoxitin treatment, or were present when cefoxitin therapy was discontinued, in 25 (1 -4%) of the 1749 patients. The adverse experiences were considered drug related in 14 of these 25 patients: 3 had abnormal renal function, 3 abnormal hepatic function, 5 had eosinophilia, 1 had decreased
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117 patients, 12(10%) were transferred from 0-5 to 1 0% lidocaine diluent for this reason; however, 7 of these patients had not received i.m. cefoxitin strictly in accordance with the dosage recommendations in the study protocol. In 6 of the 7 patients, the injection site had been changed daily, rather than after each dose; the seventh patient had received injections in the deltoid muscle, rather than in the gluteus or the thigh. Transfer to 1 -0 % lidocaine diluent abolished pain on injection in 6 patients, but 2 patients continued to experience mild pain and 4 others continued to experience moderate pain. Symptoms of local intolerance to i.m. cefoxitin therapy, other than pain, were observed only infrequently.
Safety and tolerance of cefoxitin
103
Table XII. Most frequently observed drug-related adverse laboratory experiences in i.v. studies with cefoxitin Adverse experience
Patients with drug-related adverse experience
1612 826
47 (2-9%) 20(2-4%)
1625 1313 1631 1605 1026 1128 1562
49(3-0%) 41(3-1%) 24(1-5%) 6(0-4%) 16(1-6%) 12 (11%) 11 (0-7%)
SGOT, aspartate transferase; SGPT, alanine transfcrase; LHD, lactic dehydrogenase; BUN, blood urea nitrogen. •Patients tested before and during or after therapy.
haemoglobin, 1 had leukopenia, and 1 had leukocytosis. In the 175 patients who received i.m. cefoxitin, drug-related eosinophilia was reported in 3 patients (1 -7 %) and abnormally increased liver function in 4 patients (2-3%). No drug-related abnormalities in kidney function or urinalysis data were reported in these studies.
Discussion On the basis of extensive laboratory analyses of haematopoietic, renal, and hepatic function, cefoxitin sodium appears to be a safe drug. A small proportion of patients receiving cefoxitin may develop a positive direct Coombs test, eosinophilia, or an increase in liver enzymes. Changes in liver function are difficult to evaluate in patients who have serious bacterial infection and, frequently, a chronic background disease. The possibility cannot be eliminated that some of the changes in liver function observed during these clinical studies may have been related to cefoxitin therapy. Changes in laboratory test values for individual patients during cefoxitin therapy were generally those expected during the healing of an infectious disease. Between-group differences in changes in mean laboratory values do not have any clear clinical significance, but suggest that cefoxitin and cephalothin are similarly free of toxic effects.
Conclusion Based on data from 108 studies conducted throughout the world in 2277 patients, 1924 of whom received cefoxitin (i.v. in 1749 patients and i.m. in 175), it is concluded that parenteTally administered cefoxitin is well tolerated by the majority of patients (more than 90%). Drug-related adverse clinical reactions occurred in about 8 % of the patients. The adverse clinical experiences most frequently observed were rash (2-2% incidence) and local intolerance, including thrombophlebitis, at the site of administration (5-3% incidence). From laboratory data related to haematopoietic, renal, and hepatic function, it appears that cefoxitin has neither unusual nor significant toxic effects on the major
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Eosinophilia Positive direct Coombs test Increased: SGOT SGPT Alkaline phosphatase Serum bilirubin LDH BUN Serum creatinine
Total no.
104
C. van Winzum
body systems. During therapy with cefoxitin, some patients developed a positive direct Coombs test (2-4%), eosinophilia (2-9%), or an increase in liver enzymes (about 3%). Cefoxitin is a highly safe and well-tolerated therapeutic agent for the clinical management of bacterial infections, and is a significant addition to the roster of currently available antibiotics. References
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Darland, G. & Birnbaum, J. Cefoxitin resistance to/Mactamase: a major factor for susceptibility of Bacteroides to the antibiotic. Antimicrobial Agents and Chemotherapy 11: 725-734 (1977). Onishi, H. R., Daoust, D. R., Zimmerman, S. B., Hendlin, D. & Stapley, E. O. Cefoxitin, a semisynthetic cephamycin antibiotic: resistance to )J-lactamase inactivation. Antimicrobial Agents and Chemotherapy 5: 38-48 (1974). Schrogie, J. J., Davies, R. O., Kwan, K. C , Rogers, D., Holmes, G. I., Skeggs, H. & Martin, C. M. Bioavailability and pharmacokinetics of cefoxitin. Proceedings, 10th International Congress on Chemotherapy, Zurich, Sept. 18-23, 1977. In the press (1978). Wallick, H. & Hendfin, D. Cefoxitin, a semisynthetic cephamycin antibiotic: susceptibility studies. Antimicrobial Agents and Chemotherapy 5: 25-32 (1974).
Clinical safety and tolerance of cefoxitin sodium: an overview
C. van Winzum
Based on data from 108 studies conducted throughout the world in 2277 patients, 1924 of whom received cefoxitin (i.v. in 1749 patients and i.m. in 175), it is concluded that parenterally administered cefoxitin sodium is well tolerated by the majority of patients (more than 90%). Drug-related adverse clinical reactions occurred in about 8 % of the patients. The adverse clinical experiences most frequently observed were rash (2-2% incidence) and local intolerance, including thrombophlebitis, at the site of administration (5-3% incidence). From laboratory data related to haematopoietic, renal, and hepatic functions, it appears that cefoxitin has neither unusual nor significant toxic effects on the major body systems. During therapy with cefoxitin, some patients developed a positive direct Coombs test (2-4%), eosinophilia (2-9%), or an increase in liver enzymes (ca. 3%).
Introduction Cefoxitin sodium is the first of the cephamycins, a new group of /f-lactam antibiotics. A unique feature of cefoxitin is its remarkable resistance to inactivation by yS-lactamases (Onishi, Daoust, Zimmerman, Hendlin & Stapley, 1974; Wallick & Hendlin, 1974; Darland & Birnbaum, 1977). In the animal species studied, large doses of parenterally administered cefoxitin were well tolerated; the antibiotic had the degree of safety characteristic of the presently available /Mactam antibiotics (preclinical and toxicologic data on file at Merck Sharp & Dohme Research Laboratories). Cefoxitin was well tolerated by the 58 healthy volunteers who received it in six Phase I clinical pharmacology studies. After single intravenous doses of 0-5, 1 0 and 2 0 g of cefoxitin, adverse clinical reactions were reported for 4 subjects. None of these was serious. It was observed in these Phase I studies that cefoxitin reconstituted in water was not well tolerated at the injection site after single intramuscular doses of 0-5 or 10 g. Reconstitution of cefoxitin in 0-5% lidocaine HC1 improved tolerance to cefoxitin at the site of i.m. injection significantly; use of 1 0 % lidocaine HC1 did not further improve local tolerance. The majority of subjects studied had no pain or only mild pain at the injection site after i.m. doses of 0-5,1 0 or 2 0 g of cefoxitin reconstituted in 0-5 or 1 -0 % lidocaine HC1 (Schrogie et al., 1978). The safety and tolerance of cefoxitin were evaluated on the basis of data from 108 clinical studies conducted throughout the world, involving a total of 2277 patients. All 1924 patients who received cefoxitin parenterally (Table I) have been included in the analyses of safety and tolerance. 91
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Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey, U.S.A.
92
C. van Winzum Table I. Total patient population Nu m
, Jer of studies
Nature of study Comparative i.v. studies Outside U.S.A.
21 6 6 6
Number of patients Cefoxitin Cephalothin Cefazolin
3,3
Noncomparative i.v. studies Outside U.S.A. Within U.S.A. Subtotal noncomparative studies
27 37 27 37 64 64
430 931 430 931 1361 1361
— — — —
— — —
430 931 1361
Subtotal i.v. studies
97 97
1749
290 290
63
2102
9 9 22
147 147 28 28 1924
— — — 290
— — 63
147 28 2277
Noncomparative studies Outside U.S.A. i.m. Outside U.S.A. i.v.—i.m. Total
108
107 107 290 290
— 63
371 123
—
247
63
741
The results presented in the report relate only to clinical experience with dry, microcrystalline sodium cefoxitin, the pharmaceutical formulation that will be marketed. This formulation is stable for at least 2 years when stored below 30° in the dry state. The data analyzed for this report exclude patients whose case records had not been received in the head office of Merck Sharp & Dohme Research Laboratories by 15 July 1977, for studies performed overseas, and by 15 November 1977, for studies performed within the United States. Patient population and methods
The total number of studies conducted throughout the world and the numbers of patients in the various treatment groups are shown in Table I. The total of 1749 patients who received cefoxitin i.v. included 1361 who participated in the 64 noncomparative studies and 388 who were in cefoxitin-treated groups of the 33 comparative studies (versus cephalothin or cefazolin). In 5 of the 6 studies performed within the U.S.A., the randomization procedure specified in the study protocol was not followed. Consequently, the two treatment groups in the U.S.A. studies differed in some important aspects in a statistically significant way: the incidence of background diseases, physiologic impairments, or both, was higher in the cefoxitin-treated group than in the cephalothin-treated gTOup. Alcoholism, neoplastic disease, negative nitrogen balance, and renal insufficiency were present in a significantly higher proportion of cefoxitin-treated patients. These differences are explained by the fact that an excess of approximately 30 seriously ill patients was enrolled in the cefoxitin-treated group. Of these 30 patients, 22 were suffering from infection by cephalothin-resistant, often multiresistant, cefoxitin-sensitive
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Subtotal comparative studies
188 60 140 140 388 388
Within U.S.A.
183 183
Total
Safety and tolerance of cefoxitin
93
Results Intravenous studies a. Incidence of adverse clinical experiences. The overall incidence of adverse clinical experiences in the i.v. comparative and noncomparative studies is summarized in Table II. Adverse clinical experiences that the investigators considered to be drug related (possible, probable, or definite relationship) were reported for 138 (7-9%) of the 1749 cefoxitin-treated patients, compared with 29 (10 %) of the 290 cephalothin-treated patients and 10 (15-9%) of the 63 cefazolin-tTeated patients.
Table II. Overall incidence of adverse clinical experiences in i.v. comparative and noncomparative studies with cefoxitin, cephalothin and cefazolin Total number of patients
Cefoxitin 1749
Cephalothin
Cefazolin
290
63
Number of patients with non-drug-related adverse experiences Number of patients with drug-related* adverse experiences
166(9-5%)
17(5-9%)
2(3-2%)
138(7-9%)
29(10-0%)
10(15-9%)
Total number of patients with adverse experiences
304(17-4%)
46(15-9%)
12(19-1%)
•Drug related: possibly, probably, or definitely related to study drug, in the opinion of the investigator.
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pathogens. In the context of these comparative studies, these patients could only be treated with cefoxitin. In the comparative studies, patients were to be selected in such a way that they could receive either cefoxitin or the control agents, since allocation of patients to treatment groups was randomized. This meant that the causal pathogens had to be sensitive to both cefoxitin and the control agent, cephalothin or cefazolin. As a consequence, the 741 patients of the comparative studies were, in general, less severely ill—in terms of infections disease and of complicating background conditions—than the 1361 patients of the noncomparative studies. The safety and tolerance of i.m. cefoxitin were evaluated on the basis of data from 11 clinical studies conducted overseas, involving a total of 175 patients. In 9 of these studies, a total of 147 patients was treated with i.m. cefoxitin. In the remaining 2 studies, a total of 28 patients was treated first with i.v. cefoxitin (5 to 7 days) and then with i.m. cefoxitin. The severity of illness in the 175 patients who received i.m. cefoxitin was, in general, mild to moderate. The dosage of i.v. cefoxitin was, in the majority of patients, 2 g (range 1 to 4 g) every 8 h. In the comparative studies, i.v. cephalothin was also given at that dosage and on the same schedule, but the dosage of i.v. cefazolin was 1 g every 8 h in almost all patients. The infusion time for these antibiotics was 30 min (range 5 to 120 min) in the majority of patients. The mean duration of i.v. treatment was about 8 days (range 5 to 14 days) in most patients. Cefoxitin was reconstituted in 0-5 or 1 0 % lidocaine HC1 solution for i.m. administration at a dosage of 1 g every 8 h. The mean duration of i.m. treatment was about 7 days (range 3 to 14 days).
Table III. Studies with intravenous cefoxitin. Drug-related adverse experiences, by body system and intensity Total at Patients Patients Patients
Treatment group—cefoxitin 1749 1749 1611 (921%) 138 (7-9%)
study start in time range without adverse experience with any adverse experience
Adverse experiences by body system
Moderate
Severe
— 1 2 7
2 19
1 2 3 1 1 1 1 5 16
2 1
4 1
—
— 1 1
—
—
Total
Per cent
22 1 3 6 1
46 7 39 1
1-3 01 01 0-3 0-6 01 01 01 01 2-6 0-4 2-2 01
3 2 1
0-2 01 01
57
3-3 01 01 01 01 0-2 01 01 2-2 01 01 0-5 0-2 01 01 01 01
1 1 3 1
\
13
3 1
3 2 1
3 1 1 1
38 1 2 8 3 2 1 1 2
1 1 22 2 2
1 — 1 6
1 1 —
—
7 3 5
1 — — 1
— 1 — 1
20 1 13 3 5 1 1 1
11 01 0-7 0-2 0-3 01
2 1 1
01 01
01 01
01
Note: This table contains counts of patients; although a patient might have had two or more adverse experiences for one body system, he was counted only once in that body system total. Therefore, the sum of individual adverse experiences may not equal the total for the body system. A similar distinction exists between the body system totals and the number of patients with adverse experiences.
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Body as a whole Chest pain Oedema Fever Headache Pain—back Drug fever Hypersensitivity Infection, fungal Integumentary system Pruritus Rash Stomatitis Respiratory system Dyspnoea Hyperventilation Cardiovascular system Arrhythmia Bradycardia Cyanosis Hypertension Hypotension Palpitations Tachycardia Thrombophlebitis Angina pectoris Vasodilation Infused vein—pain Infused vein—induration Infused vein—erythema Infused vein—exudation Infused vein—inflammation Infused vein—infection Digestive system Constipation Diarrheoa Nausea Vomiting Tongue discoloration Urogenital system Renal failure Nervous system Dizziness Vertigo
No. of points with recorded maximum intensity
Mild
95
Safety and tolerance of cefoxitin
All drug-related adverse clinical experiences reported for the 1749 patients treated with i.v. cefoxitin are further specified by body system and by severity (maximum recorded intensity) in Table III. All drug-related adverse clinical experiences reported in the comparative studies are similarly specified in Table IV for the cephalothin-controlled studies and in Table V for the cefazolin-controlled studies. Table IV. Cefoxitin and cephalothin. Drug-related adverse clinical experiences in 27 Phase II and Phase III comparative i.v. studies in the U.S.A. and overseas Cefoxitin
290
328
Total patients Patients with any adverse experience
29(10%)
Adverse experiences by body system
Pts. c max. intensity Mi Mod Sev Tot %
21 (6-4%)
Body as a whole Chills Oedema Fever Pain in back
3 1
10 0-3
3
10
1 3 1
0-3 0-9 0-3
Integumentary system Rash Erythema multiforme Glossitis/black tongue
6 4 1 1
20
3 3
0-9 0-9
Musculoskeletal system Myalgia "
1 1
0-3 0-3
1 1
0-3 0-3
00
Pts. c max. intensity Mi Mod Sev Tot % 1-2
1-4 0-3 0-3
Respiratory system Dyspneoa 12 1
Blood/lymph system Phlebitis
2-4 2-4
Digestive system Diarrheoa Vomiting Urogenital system Renal failure Nephritis
3 2 1
2-4 0-3 0-3 0-9
2
2 1 1
4 1 1
1-2 0-3 0-3
2
1
7 7
21 21
1 1
0-3 0-3
1 1
0-3 0-3
41 10 0-3 20 1-4 10 0-3
1 1 2
1 1
Ul — —
Cardiovascular system Cyanosis Hypotension Thrombophlebitis Thrombosis Infused vein—pain Infused vein—induration Infused vein—erythema Infused vein—irritation
1
10 0-7 0-3
2
1
0-3
1 1
0-3
See note on Table III. Mi, mild; Mod, moderate; Sev, severe; Tot, total.
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Cephalothin
96
C. van Winzum
Because one patient can have more than one adverse experience, the total number of incidents can exceed the number of patients. Table III shows that 167 incidents of adverse experience were reported for 138 of the 1749 patients given i.v. cefoxitin. Of the 167 incidents, 71 (43%) were clinically mild, 69 (41 %) were moderate, and 27 (16%) were severe. Table IV shows that in the comparative studies with cephalothin, 21 (6-4%) of the 328 cefoxitin-treated patients had 29 drug-related adverse clinical experiences, compared with 29 (10%) of the 290 cephalothin-treated patients, who had 40 drug-related adverse clinical experiences. The intensities of these experiences were: Mild
Moderate
Severe
Total
7 6
13 20
9 14
29 40
Table V shows that in the comparative studies with cefazolin, 6 (10%) of the 60 cefoxitintreated patients had 6 drug-related adverse clinical experiences, compared with 10 (15-8%) of the 63 cefazolin-treated patients, who had 12 drug-related adverse clinical experiences. The intensities of these experiences were: Mild 4 6
Cefoxitin Cefazolin
Moderate 1 5
Severe 1 1
Total 6 12
Table V. Cefoxitin and cefazolin. Drug-related adverse clinical experiences in 6 Phase II comparative i.v. studies overseas
Total patients Patients with any adverse experience Adverse experiences by body system
Cefoxitin
63
60
10(15-8%)
6(10%)
Pts. c max. intensity Mi Mod Sev Tot % — 1
Body as a whole Fever Hypersensitivity Integumentary system Rash Stomatitis
Cefazolin
1 1
— 3
1
4 4
1-6 1-6 6-3 6-3
Pts. c max. intensity Mod Sev Tot % —
1
1-7
1
1
1-7
—
2 1 1
3-3 1-7 1-7
1
1 — 1
1 1
1-6 1-6
— 2
5 5
7-9 7-9
Digestive system Diarrheoa
—
0
Psychiatric Depression
— 1
Respiratory system Dyspneoa Cardiovascular system Thrombophlebitis Vasodilation
Mi
3
0
—
2 1 1
3-3
1 1
1-7 1-7
1 1 — 1
1 1
—
1-6 16
Sec note on Table 111. Mi, mild; Mod, moderate; Sev, severe; Tot, total.
1-7 1-7
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Cefoxitin Cephalothin
Safety and tolerance of cefoxitin
97
Table VI. Mortality in all studies Cefoxitin Type of study Comparative i.v. Noncomparative i.v. Subtotal i.v. l.m.
Total
Cephalothin
Cefazolin
No. of patients
Deaths
No. of patients
Deaths
18(4-6%) 88(6-5%) 106(61%) 2(11%)
290
10(3-4%)
63
1(1-6%)
290
10(3-4%)
63
1(16%)
108(5-6%)
290
10(3-4%)
63
1(16%)
No. of patients
Deaths
388 1361 1749 175 1924
Relationship of cefoxitin treatment to death could not be excluded in 1 case, a 37-yearold man with metastatic choriocarcinoma and renal thrombosis who developed signs of renal insufficiency post-operatively. He also received canceT chemotherapy. The patient died of renal failure several days after cefoxitin treatment had been discontinued. No autopsy was performed. Mortality in the comparative studies was 4-6% in the cefoxitin group, 3-4% in the cephalothin group, and 1 -6% in the much smaller cefazolin group. Mortality in the noncomparative studies, which involved more severely ill patients, was, as expected, slightly higher (6-5%) than, in the comparative studies. Because evaluation of the therapeutic utility of cefoxitin in 'problem' patients was emphasized in studies in specialized centers in the U.S.A., the mortality rate was higher in i.v. studies in the U.S.A. than in i.v. studies overseas: Number of patients Number of deaths
U.S.A. 1071 89(8-3%)
Overseas 678 17(2-5%)
Total 1749 106(61%)
c. Discontinuation of treatment because of adverse clinical experiences. Treatment was discontinued because of adverse clinical experiences in 69 (3-9%) of the 1749 patients
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These data show that cefoxitin was, in general, at least as well tolerated as were cephalothin and cefazolin at equipotent i.v. daily dosages. b. Mortality. An i.v. antibiotic, such as cefoxitin, will frequently have to be administered to severely ill, often terminally ill, patients, or to patients with impaired immune response caused by metastatic malignancies, severe diabetes mellitus, renal insufficiency, or the use of immunosuppressive drugs. In order to gain broader experience with the potential utility of cefoxitin in the treatment of such conditions, studies were conducted in specially selected institutions having infectious-disease units, particularly in the United States. These studies included patients with infections caused by Bacteroides fragilis and cephalothin-resistant, cefoxitin-sensitive aerobic pathogens. Inevitably, a number of patients did not survive, despite appropriate antibiotic treatment (Table VI). As Table VI shows, 106 (61 %) of the 1749 patients who received i.v. cefoxitin died, either during treatment or within 14 days after discontinuation of cefoxitin treatment. In 86 of these patients, death was due primarily to the severe background disease; in 19 patients, death was due primarily to the infection, although serious background disease may have played a contributory role in at least 12 of these patients.
98
C van Winzum
Table VII. Intravenous cefoxitin. Discontinuation of treatment with cefoxitin because of drug-related adverse clinical experiences Adverse experience Rashes Local intolerance Pruritus Nausea-vomiting Diarrheoa Fever Other Total
Number of patients 27(1-5%) 11(0-6%) 4 3 2 5 5 57/1749(3-3%)
As may be seen in Table III, the majority of drug-related adverse clinical experiences in patients who received i.v. cefoxitin related to the body as a whole, to the integumentary system, and to the cardiovascular system. Body as a whole Special precautions were taken to avoid anaphylactoid reactions. In the course of these clinical studies, 3 patients exhibited adverse clinical effects that were initially reported as anaphylactic reactions. Each event was investigated promptly and vigorously. Follow-up studies included chest X-rays, electrocardiogram, radioisotope lung scan, and serum enzyme determinations. On the basis of these studies, it became apparent that these 3 patients had not had anaphylactic reactions, but pulmonary embolisms that gave rise to clinical signs closely resembling those of anaphylaxis. No confirmed anaphylactic reaction has yet been reported. Fever of different intensities occurred in 6 (0-3%) of the 1749 patients. Drug feveT, specifically, was reported in 1 patient (01 %), and use of cefoxitin in that patient was discontinued. Headache occurred in 11 patients (0-6%) and was mild or moderate in 10 of these. All 11 incidents of headache were reported from a single study. Integumentary system Forty-six (2-6%) of the 2749 patients had adverse experiences involving the integumentary system. Rash was the most common of these, occurring in 39 patients (2-2%). The
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who received i.v. cefoxitin. These adverse experiences were considered to be drug related (possible, probable, or definite relationship) in 57 of the 69 patients (Table VII). Rashes in 27 patients and intolerance at the infusion site in 11 patients were the most frequently cited reasons for discontinuing i.v. cefoxitin therapy. In the comparative i.v. studies with cephalothin, treatment was discontinued in 5 (1-5%) of the 328 cefoxitin-rreated patients and in 5 (1-7%) of the 290 cephalothintreated patients because of adverse clinical experiences. In the comparative i.v. studies with cefazolin, treatment was discontinued because of adverse clinical experiences in 3 (50%) of the 60 cefoxitin-treated patients and in 4 (6-3%) of the 63 cefazolin-treated patients. These results support the view that cefoxitin is not appreciably different from cephalothin and cefazolin in the frequency with which treatment had to be discontinued because of adverse clinical experiences.
Safety and tolerance of cefoxitin
99
Cardiovascular system Adverse clinical experiences affecting the cardiovascular system were reported in 57 (3-3 %) of the 1749 patients (68 separate incidents). The majority of these events (55) were local intolerance reactions that were categorized by the investigators as adverse clinical experiences. Thirty-eight patients (2-2%) developed thrombophlebitis of the infused vein. Other patients had pain, induration, erythema, exudation, inflammation, or infection at the site of infusion, sometimes with thrombophlebitis. Local tolerance of cefoxitin is discussed in more detail elsewhere in this report. Other adverse clinical experiences affecting the cardiovascular system were: angina pectoris, cyanosis, hypertension, palpitations, and bradycardia, each occurring in 1 patient (0 1%); hypotension in 4 patients (0-2%); and vasodilation in 2 patients (0-1 %). Treatment was discontinued in all the aforementioned patients except 1 with hypertension and 1 with vasodilation. Digestive system Twenty (1 -1 %) of the 1749 patients had adverse reactions involving the digestive system. Diarrheoa of mild or moderate intensity was most common, occurring in 13 patients (0-7%), and caused discontinuation of treatment in 2 patients. Nausea of moderate intensity occurred in 3 patients (0-2%), leading to discontinuation of treatment in all. Moderate vomiting occurred in 5 patients (0-3%), 2 of whom were taken off treatment. Mild 'tongue discoloration* occurred in 1 patient (01 %). Other body systems Adverse experiences affecting other body systems were uncommon. The nervous system was involved in 2 patients (01 %) and the respiratory system in 3 (0-2%). There were no reports of adverse experiences affecting the musculoskeletal, haematologic/lymphatic, or endocrine systems. No drug-related psychiatric disturbances weTe reported. The 1 patient who developed renal failure that may have been related to cefoxitin was discussed earlier in the section entitled 'Mortality'. Local tolerance of i.v. cefoxitin therapy It is well known that i.v. infusions of most ^-lactam antibiotics produce local reactions, including thrombophlebitis, in a small proportion of patients treated for several days. As part of the evaluation of cefoxitin, investigators assessed each patient's tolerance of
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typical rash exhibited by these patients was diffuse, maculopapular, and erythematous, infrequently pruritic, and transient, leaving no residual skin changes. Rashes were considered severe in 4 patients, but serious in only 1. Rashes considered related to cefoxitin led to discontinuation of therapy in 27 patients. Cefoxitin was discontinued in 4 additional patients with rashes not related to drug administration. The high proportion of patients in whom the drug was discontinued because of the development of a rash no doubt reflected the concern of investigators about hypersensitivity to (5-lactam antibiotics and, particularly, about the potentially more serious manifestations of such hypersensitivity. As mentioned earlier, anaphylaxis was not observed in the cefoxitin study population. Mild-to-moderate pruritus occurred in 7 patients (0-4%), only 1 of whom also had a rash. Cefoxitin was discontinued in 4 of these patients. Severe stomatitis developed in 1 patient (01 %).
100
C. van Winzum
Table V1D. Overall local tolerance of i.v. cefoxitin therapy Degree of tolerance
Number of patients
Phlebitis
Well tolerated Moderately well tolerated Poorly tolerated
1469(87-5%) 161(9-6%) 48(2-9%)
0 61 28
1678
89
Total
The results of the comparative studies indicated that cefoxitin was at least as well tolerated at the infusion site as cephalothin and cefazolin (Tables IV and V). Detailed analysis of the data showed that the duration of each infusion and of tetal therapy had no significant effect on the frequency or intensity of local intolerance and thrombophlebitis. Various infusion systems were used for i.v. cefoxitin therapy: indwelling polyethylene catheters; conventional i.v. systems with large-bore needles, smallbore needles, or butterfly needles; and cannulas with heparin. The data for local tolerance were, therefore, analyzed with respect to the infusion systems used. As shown in Table IX, most patients received i.v. cefoxitin either through an indwelling polyethylene catheter (514 patients) OT a butterfly needle (588 patients). Thirty-six (7 0%) of the patients given infusions through an indwelling polyethylene catheter developed thrombophlebitis, compared with 25 (4-3%) of the patients given infusions through a butterfly needle. This difference is statistically significant (P < 005). Table IX also shows that 25 (4-9%) of Table IX. Effect of infusion system on patient tolerance of i.v. cefoxitin therapy Infusion system Indwelling polyethylene catheter Large-bore needle Small-bore needle Butterfly needle Cannula with heparin Two or more systems used Totals
Well tolerated
Moderately well tolerated
Poorly tolerated
443 97 241 538 88 62
46(18)' 19(1) 32(11) 39 (20) 7(3) 18(8)
25(18) 6(2) 3(0 11 (5)
1469
161 (61)
1
2(2) 48(28)
'Numbers in parentheses indicate patients who developed thrombophlebitis.
Total 514 (36; 7%) 122 (3; 2-5%) 276 (12; 4-3%) 588 (25; 4-3%) 96(3; 31%) 82(10; 12-2%) 1678 (89; 5-3%)
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i.v. cefoxitin after therapy had been concluded. Occurrences of thrombophlebitis were also recorded. Of the 1678 patients for whom data were analyzed, i.v. infusion of cefoxitin was well tolerated by 1469 (87-5 %), moderately well tolerated by 161 (9-6%), and poorly tolerated by 48 (2-9%). Thrombophlebitis in the infused vein was reported in 89 (5-3%) of the 1678 patients: in 61 (38 %) of those patients who had tolerated cefoxitin moderately well and 28 (58 %) of those who had tolerated cefoxitin poorly (see Table Vni). Eleven patients were withdrawn from the studies because of local intolerance (Table VII). Investigators reported thrombophlebitis as an adverse clinical experience in only 38 of the 89 patients who developed signs or symptoms of thrombophlebitis, i.e., they tended to under-report this condition.
Safety and tolerance of cefoxitin
101
514 patients given infusions through an indwelling polyethylene catheter were judged by the investigators to have tolerated the infusion poorly, compared with 11 (1-8 %) of 588 patients given infusions through a butterfly needle. This difference in local tolerance is highly significant (P < 001). The incidence of thrombophlebitis in patients given infusion through an indwelling polyethylene catheter is also significantly greater (P < 001) that in all patients for whom other systems were used: 36 (7%) of 514 patients given infusions through an indwelling polyethylene catheter compared with 43 (3-9%) of 1082 patients using all other systems, as shown in Table X.
Occurrence of thrombophlebitis
Infusion system Indwelling polyethylene catheter Butterfly needle All other systems (excluding 82 patients in whom 2 or more systems were used)
Yes
No
Total
36(7-1%) 25 (4-2%)*
478(93%) 563(95-8%)
514 588
43t
1039
1082
•Indwelling catheter vs butterfly needle, P < 0 05. flndwelling catheter vs all other systems, P < 0-01.
From these data, it appears that the incidence of thrombophlebitis may be reduced and local tolerance of i.v. cefoxitin therapy can be improved if infusion through indwelling polyethylene catheters is avoided. Intramuscular studies a. Incidence and nature of adverse clinical experiences. Adverse clinical experiences were reported in 6 (3-4%) of the 175 patients admitted to these studies, and were considered drug related in 4. None of the experiences was considered serious. Therapy was discontinued in 1 patient because of adverse clinical experience considered by the investigator to be definitely related to cefoxitin therapy. A mild 'hypersensitivity reaction' was reported after 2 days of cefoxitin treatment in a 30-year-old woman with a phlegmonous infection of the right forearm. The reaction consisted of fever, intense pain in the infected arm, nausea, pruritus, maculopapular rash, and cervical lymphadenitis. After surgical drainage, the patient's clinical condition improved rapidly. Fever was reported in 2 patients, 1 of whom also had myalgia. Pruritus occurred in 1 patient. b. Mortality. Two patients died within 2 weeks after termination of cefoxitin therapy. The causes of death (myocardial infarction and stroke) were not related to cefoxitin treatment. c. Local tolerance. The investigators' oveT-all assessments of tolerance of cefoxitin at the i.m. injection site are summarized in Table XI. Intramuscular cefoxitin therapy was well tolerated by about 90% of the patients, regardless of the concentration of lidocaine diluent used to reconstitute the cefoxitin solution. No patient experienced pain on solution so severe as to require his withdrawal from the study. Investigators who initiated treatment with cefoxitin reconstituted with 0-5% lidocaine solution were permitted to change the diluent to 1 0 % lidocaine solution in ordeT to improve local tolerance. Of
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Table X. Frequency of thrombophlebitis in cefoxitln-treated patients: effect of indwelling polyethylene catheters
102
c. van Winzum Table XI. Tolerance of cefoxitin at i m. injection site Number and per cent of patients Diluent Over-all tolerance Well tolerated Moderately well tolerated Poorly tolerated Total
0-5% Lidocaine
1-0% Lidocaine
108 (92%) 8 (7%) 1 (1%)
51 (88%) 7 02%) 0
117
58
Drug-related adverse laboratory experiences (both i.v. and i.m.) Most of the changes in laboratory test values for individual patients during cefoxitin treatment were consistent with those expected during the healing of an infectious disease, such as decrease in total white blood cell count, decrease in neutrophil count, increase in lymphocyte count, and improvement in liver and kidney function test values. Because of this healing process, statistically significant within-group changes from baseline (prestudy) in the mean values of many of the laboratory tests occurred during treatment with cefoxitin, cephalothin, or cefazolin. Statistically significant between-group differences in the extent of change from baseline in the mean values of several laboratory tests occurred during treatment. In the comparative studies with cephalothin conducted outside the United States, the cefoxitintreated group showed a significantly greater decrease from baseline values in serum creatinine and a significantly greater increase in eosinophil count than did the cephalothintreated group. In the comparative studies with cephalothin conducted in the U.S.A., the cefoxitin-treated group showed a significantly greater decrease in bilirubin, a significantly greater decrease in SGOT, and a significantly greater increase in urine casts than did the cephalothin-treated group. The most frequently observed drug-related adverse laboratory experiences in the i.v. studies with cefoxitin, which are summarized in Table XII, included increased SGOT ( 3 % of the patients tested) and SGPT ( 3 1 %), eosinophilia (2-9%), and positive direct Coombs test (2-4 %). Increased haemolysis was not reported in any patient with a positive direct Coombs test. Adverse laboratory experiences led to discontinuation of i.v. cefoxitin treatment, or were present when cefoxitin therapy was discontinued, in 25 (1 -4%) of the 1749 patients. The adverse experiences were considered drug related in 14 of these 25 patients: 3 had abnormal renal function, 3 abnormal hepatic function, 5 had eosinophilia, 1 had decreased
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117 patients, 12(10%) were transferred from 0-5 to 1 0% lidocaine diluent for this reason; however, 7 of these patients had not received i.m. cefoxitin strictly in accordance with the dosage recommendations in the study protocol. In 6 of the 7 patients, the injection site had been changed daily, rather than after each dose; the seventh patient had received injections in the deltoid muscle, rather than in the gluteus or the thigh. Transfer to 1 -0 % lidocaine diluent abolished pain on injection in 6 patients, but 2 patients continued to experience mild pain and 4 others continued to experience moderate pain. Symptoms of local intolerance to i.m. cefoxitin therapy, other than pain, were observed only infrequently.
Safety and tolerance of cefoxitin
103
Table XII. Most frequently observed drug-related adverse laboratory experiences in i.v. studies with cefoxitin Adverse experience
Patients with drug-related adverse experience
1612 826
47 (2-9%) 20(2-4%)
1625 1313 1631 1605 1026 1128 1562
49(3-0%) 41(3-1%) 24(1-5%) 6(0-4%) 16(1-6%) 12 (11%) 11 (0-7%)
SGOT, aspartate transferase; SGPT, alanine transfcrase; LHD, lactic dehydrogenase; BUN, blood urea nitrogen. •Patients tested before and during or after therapy.
haemoglobin, 1 had leukopenia, and 1 had leukocytosis. In the 175 patients who received i.m. cefoxitin, drug-related eosinophilia was reported in 3 patients (1 -7 %) and abnormally increased liver function in 4 patients (2-3%). No drug-related abnormalities in kidney function or urinalysis data were reported in these studies.
Discussion On the basis of extensive laboratory analyses of haematopoietic, renal, and hepatic function, cefoxitin sodium appears to be a safe drug. A small proportion of patients receiving cefoxitin may develop a positive direct Coombs test, eosinophilia, or an increase in liver enzymes. Changes in liver function are difficult to evaluate in patients who have serious bacterial infection and, frequently, a chronic background disease. The possibility cannot be eliminated that some of the changes in liver function observed during these clinical studies may have been related to cefoxitin therapy. Changes in laboratory test values for individual patients during cefoxitin therapy were generally those expected during the healing of an infectious disease. Between-group differences in changes in mean laboratory values do not have any clear clinical significance, but suggest that cefoxitin and cephalothin are similarly free of toxic effects.
Conclusion Based on data from 108 studies conducted throughout the world in 2277 patients, 1924 of whom received cefoxitin (i.v. in 1749 patients and i.m. in 175), it is concluded that parenteTally administered cefoxitin is well tolerated by the majority of patients (more than 90%). Drug-related adverse clinical reactions occurred in about 8 % of the patients. The adverse clinical experiences most frequently observed were rash (2-2% incidence) and local intolerance, including thrombophlebitis, at the site of administration (5-3% incidence). From laboratory data related to haematopoietic, renal, and hepatic function, it appears that cefoxitin has neither unusual nor significant toxic effects on the major
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Eosinophilia Positive direct Coombs test Increased: SGOT SGPT Alkaline phosphatase Serum bilirubin LDH BUN Serum creatinine
Total no.
104
C. van Winzum
body systems. During therapy with cefoxitin, some patients developed a positive direct Coombs test (2-4%), eosinophilia (2-9%), or an increase in liver enzymes (about 3%). Cefoxitin is a highly safe and well-tolerated therapeutic agent for the clinical management of bacterial infections, and is a significant addition to the roster of currently available antibiotics. References
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Darland, G. & Birnbaum, J. Cefoxitin resistance to/Mactamase: a major factor for susceptibility of Bacteroides to the antibiotic. Antimicrobial Agents and Chemotherapy 11: 725-734 (1977). Onishi, H. R., Daoust, D. R., Zimmerman, S. B., Hendlin, D. & Stapley, E. O. Cefoxitin, a semisynthetic cephamycin antibiotic: resistance to )J-lactamase inactivation. Antimicrobial Agents and Chemotherapy 5: 38-48 (1974). Schrogie, J. J., Davies, R. O., Kwan, K. C , Rogers, D., Holmes, G. I., Skeggs, H. & Martin, C. M. Bioavailability and pharmacokinetics of cefoxitin. Proceedings, 10th International Congress on Chemotherapy, Zurich, Sept. 18-23, 1977. In the press (1978). Wallick, H. & Hendfin, D. Cefoxitin, a semisynthetic cephamycin antibiotic: susceptibility studies. Antimicrobial Agents and Chemotherapy 5: 25-32 (1974).
